Intractable epilepsy remains a significant problem, and mesial temporal lobe epilepsy (MTLE), also known as chronic limbic epilepsy (CLE), is a common epilepsy syndrome that is frequently intractable. Although much is known about several regions of the brain that are associated with various stages of the seizures, little is known about the specific roles these particular regions play in the initiation of seizures, or how they interact with the other likely components of the seizure circuits. Knowing this information is essential for understanding the pathophysiology of limbic epilepsy and for targeting therapy. To examine this issue, seizures have to be studied in intact systems. In this project we propose to evaluate the roles of several candidate circuits and regions in the initiation and generalization of limbic seizures: the trisynaptic hippocampal-entorhinal loop and the medial dorsal thalamic nucleus-limbic circuits. Specifically we will test the hypotheses that one or both are key elements in the initiation of the seizures and the spread of seizures to other parts of the brain. We will also examine whether it is possible to modulate seizures by stimulation of afferents to these sites. At the end of the project we will have identified key control points in the evolution of limbic seizures and possible ways to use these points for improved therapies. PUBLIC HEALTH RELEVANCE: In this application we are proposing to examine the network interactions that underlie seizure initiation and generalization in limbic epilepsy. Although the brain regions that are involved in seizures are well known, how the different parts get involved and how they interact with one another is not well understood. This information is essential for the identification of targets for therapy and for directing future research to the key elements of the seizure circuits. We will use several in vivo seizure models, including a model with spontaneous limbic seizures to tease out the various components of each seizure stage in an intact nervous system. [unreadable] [unreadable] [unreadable]